The aci-reductone 4-(4-chlorophenyl)-2-hydroxytetronic acid compound (CHTA) possesses antilipidemic and antiaggregatory properties which differ from those of the classical phenoxyactetic acids as has been disclosed in Witiak et at. J. Med. Chem., 1988, 31:1434-1445 and Kamanna et al., Lipids, 1989, 24:25-32. Although unsubstituted 2-alkyl- and 2-acyltetronic acids are frequently found in nature, the 2-hydroxy-substituted tetronic acid redox system is found only in vitamin C and its closely related relatives (isoascorbic acid, erythroascorbic acid) and derivatives, and the macrolide antibiotic, chlorothricin.
The antiaggregatory activities of 2-hydroxytetronic acid aci-reductone compound (CHTA) are of interest since blood platelets are involved in the genesis of atherosclerosis. 2-Hydroxytetronic acid aci-reductones inhibit collagen-induced human platelet aggregation and secretion of [.sup.14 C]-serotonin in a concentration-dependent manner at equivalent doses, as reported in Witiak et al., J. Med. Chem., 1982, 25:90-93. The CHTA compound inhibits platelet function by a similar mechanism, involving arachidonic acid release. Redox analogues, such as 2-hydroxytetronic acid, function as antioxidants in membranes or interfere with free radical processes involved in the biosynthetic elaboration of cyclic prostaglandin endoperoxides (PGG.sub.2 and PGH.sub.2), and, subsequently, thromboxane A.sub.2 from arachidonic acid.
The development of dual antioxidant-arachidonic acid (AA) metabolism inhibitors may provide added benefits over existing drugs for the treatment of diseases associated with oxidative stress and inflammation. Numerous conditions including asthma, rheumatoid arthritis, irritable bowel disease (IBD), adult respiratory distress syndrome (ARDS), atherosclerosis, ischemia/reperfusion injury, restenosis, neurodegenerative disorders and initiation and promotion of carcinogenesis correlate with abnormally high levels of reactive oxygen species (ROS). Antioxidant-based therapies including both natural antioxidants (e.g., vitamin E, vitamin C and SOD), and synthetic antioxidants (e.g., 4-aryl-2-hydroxytetronic acids, 2-O-alkyl ascorbic acids, probucol and tirilazad mesylate) have been, or are currently being, investigated for the treatment of a number of these conditions.
Previously, the S-arachidonic acid aci-reductone analog (S)-3,4-dihydroxy-5 [(all Z)-3,6,9,12-octadecatraenyl]-2(5H)-furanone, was identified as a stereoselective and potent arachidonic acid metabolic inhibitor. This compound inhibits both PGE.sub.2 and LTB.sub.4 production in stimulated macrophages (IC.sub.50 =20 .mu.M) and blocks AA-induced platelet aggregation (AAIPA) with an IC.sub.50 &lt;10 .mu.M. Dual cyclooxygenase (COX) and lipoxygenase (LO) activity could be important in preventing substrate shunting in the arachidonic acid cascade. Although this compound demonstrates an encouraging biological profile, both its instability and labored synthesis render this compound less than satisfactory as a therapeutic agent.
U.S. application Ser. No. 08/915,099, and PCT/US97/14878, incorporated herein by reference, describe 5-substituted and 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones, including 5-unsubstituted biphenyl derivatives which have antilipidemic, antiaggregatory, and anti-inflammatory activities useful for the treatment of various conditions and diseases in humans and animals.
There exists a need for new therapeutic agents which exhibit the aforementioned activities. It is to this aim that the present invention is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.